Prospective Randomized Study of Cell Therapy for Metastatic Melanoma Using Short-Term Cultured Tumor Infiltrating Lymphocytes Plus IL-2 Following Either a Non-Myeloablative Lymphocyte Depleting Chemotherapy Regimen Alone or in Conjunction w/1200 TBI

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01319565
First received: March 18, 2011
Last updated: September 3, 2014
Last verified: August 2014
  Purpose

Background:

- An experimental treatment for metastatic melanoma involves cell therapy, in which researchers take white blood cells (lymphocytes) from the tumor tissue, grow them in the laboratory in large numbers, and then use the cells to attack the tumor tissue. Before receiving the cells, chemotherapy is needed to temporarily suppress the immune system to improve the chances that the tumor-fighting cells will be able to survive in the body. In some studies of cell therapy, individuals who have received total body irradiation (TBI) in addition to the chemotherapy (in order to increase the length of time that they do not produce white blood cells) seem to have a slightly better response to the treatment, but it is not known if adding radiation to the cell therapy will cause a better response for all individuals. Researchers are interested in comparing cell therapy given with the usual chemotherapy to cell therapy given with the usual chemotherapy and TBI.

Objectives:

- To compare the effectiveness of cell therapy given with chemotherapy to cell therapy given with chemotherapy and total body irradiation in individuals with metastatic melanoma.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with metastatic melanoma.

Design:

  • Participants will be screened with a physical examination, medical history, blood tests, and tumor imaging studies.
  • Participants will be divided into two groups: cell therapy with chemotherapy alone (group 1) or cell therapy with chemotherapy plus TBI (group 2).
  • All participants will provide a tumor sample from either surgery or a tumor biopsy for white blood cell collection.
  • Participants will have leukapheresis to collect additional white blood cells for cell growth and future testing, and TBI group participants will also provide stem cells to help them recover after radiation. (TBI participants who cannot provide enough stem cells will be moved to the non-radiation treatment group.)
  • Participants will have chemotherapy with cyclophosphamide (two treatments over 2 days) and fludarabine (five treatments over 5 days) starting 7 days before the cell therapy. Participants in the TBI group will also have TBI for the 3 days immediately before the cell therapy.
  • All participants will receive the white blood cells, followed by high-dose aldesleukin every 8 hours for up to 5 days after the cell infusion to help keep the therapy cells alive and active. Participants will also have injections of filgrastim to stimulate blood cell production, and participants in the TBI group will also receive their stem cells.
  • Participants will take an antibiotic for at least 6 months after treatment to prevent pneumonia, and will be asked to return for regular monitoring and followup visits for at least 5 years to evaluate the tumor s response to treatment....

Condition Intervention Phase
Metastatic Melanoma
Skin Cancer
Drug: Aldesleukin
Drug: Cyclophosphamide
Drug: Fludarabine
Drug: Young Tumor Infiltrating Lymphocytes
Procedure: 1200 Gy Irradiation
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Prospective Randomized Study of Cell Transfer Therapy for Metastatic Melanoma Using Tumor Infiltrating Lymphocytes Plus IL-2 Following Non-Myeloablative Lymphocyte Depleting Chemo Regimen Alone or in Conjunction With 12Gy Total Body Irradiation (TBI)

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Determine the objective response rate and survival of melanoma patients receiving young TL plus aldesleukin treatment following either chemo preparative regimen alon or the same chemotherapy preparative regimen plus total body radiation [ Time Frame: approximately 3 years ] [ Designated as safety issue: Yes ]

Enrollment: 102
Study Start Date: March 2011
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
Lymphodepleting Chemotherapy, Young TILand High Dose IL-2
Drug: Aldesleukin
720,000 IU/kg IV over 15 minute every eight hours (+/- 1 hour) for up to 5 days.
Drug: Cyclophosphamide
60 mg/kg/day for 2 days IV
Drug: Fludarabine
25 mg/m(2)/day IVPB daily over 15-30 minutes for 5 days.
Drug: Young Tumor Infiltrating Lymphocytes
Autologous young TIL infusion will be administered intravenously over 20 to 30 minutes (minimum 1 X 10(9) and up to a maximum of 2 X 10(11) lymphocytes).
Experimental: Cohort 2
Lymphodepleting Chemotherapy, 1200 GyRadiation, Young TIL and High Dose IL-2
Drug: Aldesleukin
720,000 IU/kg IV over 15 minute every eight hours (+/- 1 hour) for up to 5 days.
Drug: Cyclophosphamide
60 mg/kg/day for 2 days IV
Drug: Fludarabine
25 mg/m(2)/day IVPB daily over 15-30 minutes for 5 days.
Drug: Young Tumor Infiltrating Lymphocytes
Autologous young TIL infusion will be administered intravenously over 20 to 30 minutes (minimum 1 X 10(9) and up to a maximum of 2 X 10(11) lymphocytes).
Procedure: 1200 Gy Irradiation
2Gy of TBI twice a day for 3 days (total dose 12 Gy)

Detailed Description:

Background:

  • Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes can mediate the regression of bulky metastatic melanoma when administered along with high-dose aldesleukin (IL-2) following a non-myeloablative lymphodepleting chemotherapy preparative regimen consisting of cyclophosphamide and fludarabine.
  • In a series of consecutive trials using this chemotherapy preparative regimen alone or with 2 Gy or 12 Gy total body irradiation (TBI) objective response rates using RECIST criteria were 49%, 52%, and 72%, respectively. Complete regression rates in these three consecutive trials were 12%, 20%, and 40%, respectively strongly suggesting that the addition of TBI could improve the complete regression rate. Of the 20 complete regressions seen in this trial, 19 are on-going at 37 to 82 months.
  • Because of the complexity of developing selected TIL for use in adoptive transfer, we have recently developed a simplified method for producing TIL that is more applicable to use in outside institutions. Utilizing young TIL cells (sometimes with CD8 purification) in 105 patients, the objective response rate was 34% with a 6.6 % incidence of complete regressions. All patients in this trial received the cyclophosphamide fludarabine regimen alone.
  • Because of the strong suggestion that the addition of TBI to the chemotherapy regimen could increase durable, complete regression rates in patients with metastatic melanoma, we are now attempting to definitively determine whether the addition of TBI to the chemotherapy preparative regimen can improve complete response rates, and overall survival in patients receiving young TIL .

Objectives:

  • To determine, in a prospective randomized trial, the complete response rate and survival of patients with metastatic melanoma receiving ACT using young TIL plus aldesleukin treatment following either a chemotherapy preparative regimen alone, or the same chemotherapy preparative regimen plus TBI.
  • Response rate and progression free survival will be evaluated as a secondary endpoint, as will the toxicity of these two treatment regimens.

Eligibility:

-Patients who are 18 years or older must have:

  • Evaluable metastatic melanoma;
  • Metastatic melanoma lesion suitable for surgical resection for the preparation of TIL;
  • No contraindications to high-dose aldesleukin administration or total body irradiation;
  • No concurrent major medical illnesses or any form of immunodeficiency

Design:

-Patients with metastatic melanoma will have lesions resected and after TIL growth is established patients with will be prospectively randomized to receive ACT with young TIL plus aldesleukin following either a non-myeloablative chemotherapy preparative regimen or this same regimen plus TBI.

  Eligibility

Ages Eligible for Study:   18 Years to 66 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

    1. Measurable metastatic melanoma with at least one lesion that is resectable for TIL generation. The lesion must be of at least 1cm in diameter that can be surgically removed with minimal morbidity (defined as any operation for which expected hospitalization less than or equal to 7 days).
    2. Patients with 3 or less brain metastases are eligible. Note: If lesions are symptomatic or greater than or equal to 1 cm each, these lesions must have been treated and stable for 3 months for the patient to be eligible.
    3. Greater than or equal to 18 years of age and less than or equal to 66 years of age.
    4. Willing to practice birth control during treatment and for four months after receiving all protocol related therapy.
    5. Life expectancy of greater than three months
    6. Willing to sign a durable power of attorney.
    7. Able to understand and sign the Informed Consent Document
    8. Clinical performance status of ECOG 0 or 1.
    9. Hematology:
  • Absolute neutrophil count greater than 1000/mm(3)
  • Hemoglobin greater than 8.0 g/dl
  • Platelet count greater than 100,000/mm(3)

    j. Serology:

  • Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune competence and thus be less responsive to the experimental treatment and more susceptible to its toxicities.)
  • Seronegative for hepatitis B antigen, or hepatitis C antibody or antigen.

    k. Chemistry:

  • Serum ALT/AST less than three times the upper limit of normal.
  • Calculated creatinine clearance (eGFR) > 50 ml/min.
  • Total bilirubin less than or equal to 2 mg/dl, except in patients with

Gilbert s Syndrome who must have a total bilirubin less than 3 mg/dl.

l. More than four weeks must have elapsed since any prior systemic therapy at the time of randomization, and patients toxicities must have recovered to a grade 1 or less (except for alopecia or vitiligo). Patients must have stable or progressing disease after prior treatment.

Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less or as specified in the inclusion criteria.

m. Six weeks must have elapsed since any prior anti-CTLA4 antibody therapy to allow antibody levels to decline.

Note: Patients who have previously received ipilimumab or tremelimumab, anti- PD1 or anti-PD-L1 antibodies, and have documented GI toxicity must have a normal colonoscopy with normal colonic biopsies.

EXCLUSION CRITERIA:

  1. Prior cell transfer therapy which included a non-myeloablative or myeloablative chemotherapy regimen.
  2. Women of child-bearing potential who are pregnant or breastfeeding because 10 of the potentially dangerous effects of the preparative chemotherapy on the fetus or infant.
  3. Systemic steroid therapy requirement.
  4. Active systemic infections, coagulation disorders or other active major medical illnesses of the cardiovascular, respiratory or immune system, as evidenced by a positive stress thallium or comparable test, myocardial infarction, cardiac arrhythmias, obstructive or restrictive pulmonary disease.
  5. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease and AIDS).
  6. Opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immune competence may be less responsive to the experimental treatment and more susceptible to its toxicities.)
  7. History of severe immediate hypersensitivity reaction to any of the agents used in this study.
  8. History of coronary revascularization or ischemic symptoms.
  9. Any patient known to have an LVEF less than or equal to 45%.
  10. In patients > 60 years old, documented LVEF of less than or equal to 45%.
  11. Documented FEV1 less than or equal to 60% predicted tested in patients with:

    • A prolonged history of cigarette smoking (20 pk/year of smoking within the past 2 years)
    • Symptoms of respiratory dysfunction
  12. Prior radiation therapy that, in the judgment of the radiation oncologist, precludes the administration of total body irradiation.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01319565

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Steven A Rosenberg, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01319565     History of Changes
Other Study ID Numbers: 110123, 11-C-0123
Study First Received: March 18, 2011
Last Updated: September 3, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Young TIL
Metastatic Melanoma
Immunotherapy
Adoptive Cell Therapy
Skin Cancer

Additional relevant MeSH terms:
Melanoma
Skin Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Neuroendocrine Tumors
Nevi and Melanomas
Skin Diseases
Cyclophosphamide
Alkylating Agents
Antineoplastic Agents
Antineoplastic Agents, Alkylating
Antirheumatic Agents
Immunologic Factors
Immunosuppressive Agents
Molecular Mechanisms of Pharmacological Action
Myeloablative Agonists
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014